This application is filed claiming priority from co-pending Application No. GB9925457.5 filed Oct. 27, 1999.
This invention relates to the reduction of gastric acid secretion in animals including humans; to methods of treating conditions or disorders associated with or exacerbated by gastric acid secretion; to pharmaceutical compositions useful in carrying out such methods; and to the use of certain extracts and compounds in the treatment of human and non-human animals, generally mammals.
Excessive secretion of gastric acid can lead to or aggravate a number of disorders, for example oesophageal reflux disease, e.g. reflux oesaphagitis, haemorrhage in and benign ulceration of the stomach and duodenum (including those complicating NSAID therapy). These conditions tend to be more problematical in obese patients and patients with hiatus hernia. The present invention is directed, in part, to the treatment of these conditions and of ancillary indications, e.g. to provide relief of reflux-like symptoms (e.g. heartburn) and/or ulcer-like symptoms (e.g. epigastric pain) associated with acid-related dyspepsia; for general dyspeptic symptoms; and for prophylaxis of acid aspiration.
Non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin (acetylsalicylic acid), are well-known and widely used for their anti-inflammatory and antipyretic properties. A major side effect is their tendency to damage the wall of the stomach; this adverse property is acid-dependent and is generic to the NSAIDs. The present invention is also concerned with means for mitigating these adverse effects.
It is known from International Patent Publication No. WO 98/46243 that extracts of certain plants of the genus Trichocaulon or Hoodia possess appetite suppressant properties. This document also discloses certain specific compounds which possess appetite suppressant activity. Among these is the compound 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one; the structural formula of this compound is given as formula (1) in WO 98/46243. We have found that this compound is effective in reducing the secretion of gastric acid; accordingly, the compound finds application in the present invention. Derivatives of this compound are also effective in the present invention; such derivatives have the general formula 
which
R=alkyl;
R1=H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2=H, or one or more 6-deoxy carbohydrate, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed lines indicate the optional presence of a double bond in the C4-C5 or C5-C6 positions.
Thus, according to a first aspect of the present invention, there is provided a method of reducing gastric acid secretion in an animal, which comprises administering to said animal:
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula 
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
Advantageously, when R1 is an organic ester group it is tigloyl,benzoyl or anthraniloyl. In a preferred embodiment, R is an alkyl group having from one to four carbon atoms, R1 is tigloyl or anthraniloyl; and a double bond is present in the C5-C6 position.
Advantageously, R2 is trisaccharide group. The component sugars of said trisaccharide group are preferably 6-deoxy and/or 2,6-dideoxy hexoses. In some embodiments, the terminal hexose moiety is thevetosyl.
The compound may be 3-O-[-xcex2-D-thevetopyranosyl-(1-4)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one.
According to a second aspect of the present invention, there is provided a method of treating a disorder of the alimentary system in an animal, which comprises administering to the animal
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula 
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
This method can conveniently be used in the treatment of reflux oesophagitis. It is also expected to find application in the treatment of epigastric pain; dyspepsia; gastric ulceration; and acid aspiration.
According to a third aspect of the present invention, there is provided a method of protecting a mammalian gastro-intestinal tract from damage caused by a non-steroidal anti-inflammatory drug, which comprises administering an effective amount of:
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula 
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
According to a fourth aspect, the present invention provides a method of protecting a mammalian gastro-intestinal tract from damage caused by a non-steroidal anti-inflammatory drug, which comprises administering an effective amount of [3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof.
When a plant extract is used in the invention, it is presently preferred to use an extract from the plant Hoodia gordonii or Hoodia currori. Advantageously, the said extract comprises spray-dried sap of the plant Hoodia gordonii. 
The methods in accordance with this invention are applicable to the treatment of humans.
According to a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a non-steroidal anti-inflammatory drug and a compound of the formula 
wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
in which the acyl-group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
A preferred pharmaceutical composition of this type utilises the compound 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof. The pharmaceutical compositions of this invention are conveniently prepared in unit dosage form; they may also include a pharmaceutically acceptable diluent, excipient or carrier.
According to a sixth aspect of the present invention, there is provided method of treating a condition or disorder caused by or exacerbated by gastric acid secretion in an animal, which comprises administering to the animal a pharmaceutical composition as just defined. The animal may be a human.
According to a seventh aspect, the present invention provides the use of a compound of the formula 
wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94; and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position,
in the manufacture of a medicament for the treatment of a disorder caused by or exacerbated by gastric acid secretion. For such use, the compound may be 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof.
According to an eighth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of conditions and disorders caused by or exacerbated by gastric acid secretion. The condition or disorder for which the medicament is intended may be reflux oesophagitis; or gastric or duodenal ulceration; gastro-duodenal erosion; or epigastric pain.
According to a ninth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of conditions and disorders caused by or exacerbated by gastric acid secretion.
According to a tenth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of reflux oesophagitis.
According to an eleventh aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for preventing or reducing gastric damage associated with use of a non-steroidal anti-inflammatory drug.
According to a twelfth aspect, the present invention provides the use of 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof in the manufacture of a medicament for preventing or reducing gastric damage associated with use of a non-steroidal anti-inflammatory drug.
The extracts of a plant of the genus Hoodia or Trichocaulon useful in the present invention may generally be prepared by extracting sap from the plant and then spray-drying the sap. Alternatively, solvent extraction procedures may be employed. In either case, fractionation of the initial extract, e.g. by column chromatography, may follow in order to generate am extract with enhanced activity.
The extract may be prepared from plant material such as the stems and roots of plants of the genus Hoodia or the genus Trichocaulon; these genera include succulent plants which grow in the arid regions of southern Africa. Advantageously, the plant extract is obtained from one of the following species: Trichocaulon piliferum; Trichocaulon officinale; Hoodia currorii; Hoodia gordonii; and Hoodia lugardii. 
The plant material may be homogenised in the presence of a suitable solvent, e.g. a methanol/methylene chloride solvent, by means of a device such as a Waring blender. The extraction solution may then be separated from residual plant material by an appropriate separation procedure such as, for example, filtration or centrifugation. The solvent may, for example, be removed by means of a rotary evaporator, preferably in a water bath at a temperature of 60xc2x0 C. The separated crude extract may then be further extracted with methylene chloride and water before being separated into a methylene chloride extract and a water extract. The methylene chloride extract may have the solvent removed by, for example, a rotary evaporator and the resultant extract may be further purified by way of a methanol/hexane extraction. The methanol/hexane extraction product may then be separated to yield a methanol extract and a hexane extract. The methanol extract may be evaporated to remove the solvent in order to yield a partially purified active extract.
The partially purified active extract may be dissolved in methanol, and may be further fractionated by column chromatography, employing silica gel as an adsorption medium and a chloroform/30% methanol mixture as eluent. A plurality of different fractions may be obtained, and each may be evaluated, by suitable bioassaying procedures, to determine their activity. High activity fractions may be further fractionated, e.g. by column chromatography using silica gel as an adsorption medium and a 9:1 chloroform:methanol eluent. This process may be repeated using silica gel as an adsorption medium and a 9:1 ethylacetate:hexane eluent.
Alternatively, the plant product may be compressed or macerated to extract sap therefrom, then filtered to remove unwanted solids and freeze-dried. The freeze-dried sap product may then be further purified, if desired, for example using chromatographic fractionation such as described above.
The derivatives of 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one which find use in this invention are advantageously of the formula: 
in which
R=alkyl;
R1=H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2=H or alkyl;
R3=H or OH;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed lines indicate the optional presence of a further bond in the C4-C5 or C5-C6 positions;
The invention will be illustrated by the following Examples: